Antitussives are widely used for therapy of coughing associated with respiratory disorders such as cold (common cold syndrome), bronchitis and pneumonia. Antitussives can be classified into groups of central antitussives, which act on the cough center, and peripheral antitussives. The majority of antitussives presently used are the central antitussives, and they can further be classified into nonnarcotic antitussives and narcotic antitussives.
As nonnarcotic antitussives, tipepidine hibenzate, dextromethorphan hydrobromide and the like are frequently used. However, they often cause drowsiness, dizziness, headache or the like by acting on other targets than the cough center and have fewer efficacies than narcotic ones, and thus may not induce a sufficient antitussive effect.
As narcotic antitussives, codeine phosphate, dihydrocodeine phosphate and the like are commonly used and whereby relatively higher efficacy can be expected. However, they also accompany side effects such as constipation, nausea, vomiting, headache and drowsiness, and cause tolerance, dependence and drug abuse are caused, which are also problematic.
Although codeine phosphate and dihydrocodeine phosphate have the morphinan skeleton, the 6-position thereof is substituted with a hydroxy group and differ from the compound according to the present invention, which has a nitrogen-containing cyclic substituent at the 6-position thereof. Among the morphinan compounds that have a nitrogen-containing cyclic substituent at the 6-positions thereof, it has already been reported that cyclic amino-substituted compounds have antitussive effects (Patent Literature 1, 2 and 3). In addition, chemical structures of some compounds among morphinan compounds, having cyclic imido-substituents at the 6-position thereof, are disclosed, although the antitussive effect of which is not directly indicated (Non-Patent Literature 1, 2 and 3). On the other hand, it has been disclosed that the compound according to the present invention has a therapeutic effect on frequent urination and urinary incontinence (Patent Literature 4), pruritus (Patent Literature 5), and pain (Patent Literature 6) (the therapeutic use against pain was disclosed after the priority date of the present application).
However, none of these disclosures infer that the compounds according to the present invention have a remarkable antitussive effect with few side effects, so that they may be useful as antitussives.
Patent Literature 1: Japanese Patent Publication (Kokoku) No. 41-18824
Patent Literature 2: Japanese Patent Publication (Kokoku) No. 41-18826
Patent Literature 3: International Publication WO 95/03308
Patent Literature 4: International Publication WO 2004/033457 (European Publication EP1555266)
Patent Literature 5: International Publication WO 2005/094826
Patent Literature 6: International Publication WO 2006/049248
Non-Patent Literature 1: Simon C. et. al., Tetrahedron, 50, 9757-9768, 1994.
Non-Patent Literature 2: Sayre L. M. et. al., J. Med. Chem., 27, 1325-1335, 1984.
Non-Patent Literature 3: Simon C. et. al., Synth. Commun., 22, 913-921, 1992.